DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
Claims 1-20 are pending
Claims 1-20 are under consideration in the instant office action.
Priority
This application claims benefit of U.S. Provisional Application No. 62/103,020 filed on 01/13/2015 and PCT Application No. PCT/US2016/012694 filed on 01/08/2016.
Claim Objections
Claim 10 is objected to because of the following informalities: there is a duplicate comma in line 3 between “prostanoid” and “a guanylate cyclase activator”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). The court in Wands states, "Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue', not 'experimentation'" (Wands, 8 USPQ2sd 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations" (Wands, 8 USPQ2d 1404). Among these factors are: (i) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
The claims are drawn to a method of treating or preventing pulmonary hypertension comprising administering a therapeutically effective amount of compound that increases BMPR2 signaling (BMPR2 activator) to the patient with pulmonary hypertension in combination with another active agent. The breadth of the claims thus covers that the compounds are capable of preventing pulmonary hypertension, which has varied etiologies and a complicated pathogenesis.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
Within the scope of pulmonary hypertension, Bousseau et al. (Pathophysiology and new advances in pulmonary hypertension) teaches that “The underlying molecular pathogenesis of pulmonary hypertension is a complex and multifactorial process, but can be characterized by several hallmarks: inflammation, impaired angiogenesis, metabolic alterations, genetic or epigenetic abnormalities, influence of sex and sex hormones, and abnormalities in the right ventricle.” (see abstract). Bousseau et al. teaches that the patient population of pulmonary hypertension is divided into five subgroups, each with a distinct etiology (pg. 1, left and right column, bridging paragraph). Bousseau et al. teaches that even within pulmonary arterial hypertension, there exists a multitude of causes (pg. 1, right column, second paragraph). Thus, it is beyond the skill of oncologists today to determine that an agent that increases BMPR2 signaling to be effective in preventing a wide range of causes of pulmonary hypertension.
(5) The relative skill of those in the art:
Those of relative skill in the art are those with a level of skill of the authors of the references cites to support the examiner’s position (MD’s or those with advanced degrees and the requisite experience in cardiology).
(6) The amount of direction or guidance presented and (7) the presence of absence of working examples:
The specification provides working examples only for the administration of low-dose tacrolimus for the treatment of patients with WHO Group II – V pulmonary hypertension. Thus, the specification has not provided any working examples for other compounds that increase BMPR2 signaling.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed by Bousseau et al. above, the high unpredictability in the art as evidenced therein, and the lack of adequate guidance provided by the specification for all compounds that increase BMPR2 signaling, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate in the scope of the claims.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3, 5, 10-11, and 16-19 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 1 and 19 recite the broad recitation “a compound that increases BMPR2 signaling”, and the claim also recites “(BMPR2 activator)” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claims 11 and 16-18 recite the limitation "the PDE5 inhibitor" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 10 recites the limitation "the second active agent" in line 1. There is insufficient antecedent basis for this limitation in the claim.
The term “high altitude” in claim 3 is a relative term which renders the claim indefinite. The term “more normal level” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear as to the exact level of altitude that is recited.
The term “more normal level” in claim 5 is a relative term which renders the claim indefinite. The term “more normal level” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear as to the exact level of pulmonary hypertension that is recited.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-6, 10-12, 14-16, and 19-20 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Spierkerkoetter (US 2014/0135358).
Spierkerkoetter teaches methods of reducing pulmonary arterial hypertension (“PAH”) by administering compound FK506 (a.k.a. tacrolimus or fujimycin) to a mammal having PAH associated with defective BMPR2 signaling (see abstract; paragraph 0006). Spierkerkoetter teaches that “The pathophysiology of pulmonary arterial hypertension is characterized by vasoconstriction and remodeling of the pulmonary vessels.” (paragraph 0004). Spierkerkoetter teaches administering FK506 at a dosage that provides an FK506 serum concentration of 0.05 to 1 ng/ml (paragraph 0007). Spierkerkoetter teaches that tacrolimus can be administered with another active compound such as sildenafil or tadalafil (i.e. PDE inhibitor), or an endothelin antagonist such as ambrisentan (paragraphs 0008, 0037). Spierkerkoetter teaches treating PAH, including chronic PAH to reduce symptoms, which would delay clinical worsening (paragraphs 0004, 0013).
When the composition recitations are met, the desired properties are met, as any component that materially affects the composition and its properties would have to be present in the claim to be commensurate in scope (i.e. claim 5). Additionally, when the composition is delivered in the same manner as claimed, the effects of the composition would be the same such as the physiological improvements in clinical parameters, as they are a direct result of the components of the composition and the mode of administration which are met by the art, whereby the resulting properties and effects would intrinsically be met. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01.
Therefore, the reference is deemed to anticipate the instant claims above.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over Spierkerkoetter (US 2014/0135358) as applied to claims 1-6, 10-12, 14-16, and 19-20 above.
The teachings of Spierkerkoetter are presented above.
Spierkerkoetter does not teach tacrolimus present at the recited concentrations.
Even though the range for tacrolimus as taught by Spierkerkoetter is not the same as the claimed concentration, Spierkerkoetter does teach an overlapping range of concentrations, and it has been held that in the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP § 2144.05(I). Furthermore, the determination of [xxx] is well within the purview of those skilled in the art through routine experimentation, and it has been held that “it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP § 2144.05(II). It would have been obvious to one of ordinary skill in the art to optimize the concentration in order to increase the efficacy of the composition.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Spierkerkoetter (US 2014/0135358) as applied to claims 1-6, 10-12, 14-16, and 19-20 above, and further in view of Yao (Recent advances and future perspectives in therapeutic strategies for pulmonary arterial hypertension, Journal of Cardiology, 2012, 60, pp. 344-349).
The teachings of Spierkerkoetter are presented above.
Spierkerkoetter does not teach a method of pulmonary arterial hypertension by administering a therapeutically effective amount of a compound that increases BMPR2 signaling in combination with riociguat.
Yao is drawn towards advances in therapeutic strategies for PAH (see abstract). Yao teaches that riociguat provides beneficial effects including reduction in mPAP and PVR, and an increase in CO in patients with PAH and chronic thromboembolic PH (CTEPH) (left column, second paragraph, pg. 348).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to treat PAH by administering a therapeutically effective amount of a compound that increases BMPR2 signaling in combination with riociguat, as suggested by Yao, and produce the instant invention.
As stated in In re Kerkhoven, 626 F.2d 846, 205 USPQ 1069, at page 1072 (CCPA 1980):
It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (CCPA 1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art.
For these reasons, the claimed subject matter is deemed to fail to be patentably distinguishable over the state of the art as represented by the cited reference. The claims are therefore, properly rejected under 35 U.S.C. 103.In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
Claims 17-18 is rejected under 35 U.S.C. 103 as being unpatentable over Spierkerkoetter (US 2014/0135358) as applied to claims 1-6, 10-12, 14-16, and 19-20 above, and further in view of Wang et al. (Selectivity of Avanafil, a PDE5 Inhibitor for the Treatment of Erectile Dysfunction: Implications for Clinical Safety and Improved Tolerability, The journal of sexual medicine, 2012, 9(8), pp. 2122-2129).
The teachings of Spierkerkoetter are presented above.
Spierkerkoetter does not teach a method of pulmonary arterial hypertension by administering avanafil as the PDE5 inhibitor.
Wang et al. is drawn towards the safety and efficacy of avanafil (see abstract). Wang et al. teaches that avanafil, as a second generation PDE5 inhibitor, can provide advantages including higher PDE5 selectivity as well as improved tolerability given a lower incidence of adverse events (see abstract).
It would have been obvious to one of ordinary skill in the art to administer avanafil as the PDE5 inhibitor, as suggested by Corona et al., and produce the instant invention.
One of ordinary skill in the art would have been motivated to do so since Wang et al. teaches that avanafil provides improved PDE5 selectivity and a lower incidence of adverse events, with a reasonable expectation of success absent evidence of criticality of the particular steps.
Conclusion
Claims 1- 20 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDREW P LEE whose telephone number is (571)270-1016. The examiner can normally be reached Monday-Friday 9am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Renee Claytor can be reached at (571)272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ANDREW P LEE/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691